Targeting mitochondrial metabolism to promote full neural development in Allan Herndon Dudley syndrome

Allan-Herndon-Dudley syndrome (AHDS) is a rare disorder of brain development that causes severe intellectual disability and problems with movement. Affected children are wheelchair-bound, have impaired speech and limited ability to communicate. AHDS is caused by mutations in the SLC16A2 gene, which provides instructions for making a protein (MCT8) that plays a critical role in the development of the nervous system. MCT8 transports a hormone, named triiodothyronine or T3 into neurons. T3  serves for normal formation and growth of developing brain, and regulates the rate of chemical reactions (metabolism) producing energy, by acting on mitochondria, the power houses of the cells. Healthy mitochondria are necessary for full brain development. We hypothesize that mitochondria cannot function properly in neurons without T3, therefore, they produce less energy and neurons cannot develop. We aim at investigating the health status of mitochondria in AHDS; to do so, we will generate a 3D-model of brain in a dish, named organoid. This will allow us to investigate the generation of neuronal connection and the function of mitochondria in organoids cultured without T3, as it is in AHDS. We will also extract and analyse little molecules that regulate neuronal metabolism, called miRNA. Finally, we will exploit new therapeutic approaches targeting mitochondrial function by using a drug named NR, which is widely used to treat unhealthy mitochondria, and molecules that could target the miRNAs, modulating the neuronal function. Our results will shed new light on the role of mitochondria in AHDS and will open new perspectives for the therapy.